The presence of abnormal neuronal and glial filamentous inclusions composed of the microtubule-associated protein tau defines a heterogeneous group of neurodegenerative disorders, termed tauopathies (Dickson (2009)). Alzheimer's disease (AD) is currently classified as a secondary tauopathy, with tangles arising as a result of increased levels of toxic species of the amyloid-beta peptide (Aβ) (Hardy (2006)). The discovery of mutations in the microtubule-associated protein tau gene (MAPT) that cause frontotemporal lobar degeneration (FTLD) show that tau dysfunction on its own is sufficient to induce neurodegeneration (Hutton et al. (1998); Gasparini et al. (2007)), but the majority of patients with tangles lack such mutations. One example of a sporadic non-mutational primary tauopathy is tangle-predominant dementia (TPD) (Ulrich et al. (1992); Bancher and Jellinger (1994)). These exceptional patients develop neurofibrillary tangles that are regionally, morphologically, ultrastructurally and biochemically identical to those in moderate-stage AD, yet lack significant Aβ deposition as plaques (Santa-Maria et al. (2012)(1)). There are currently no effective treatments for either AD or TPD.
In the adult brain, a single gene (MAPT) on chromosome 17 gives rise to predominantly six tau isoforms (Wade-Martins (2012)). Alternative splicing of exon 10 results in tau containing either three or four tandem micro-tubule-binding domain repeats that mediate binding to tubulin (Weingarten et al. (1975)). Alternative splicing of exons 2 and 3 also occurs. Tau expression is not limited to neurons, as its presence in oligodendrocytes and astrocytes has also been observed (Binder et al. (1985); Chin and Goldman (1996)). Tau is found in somatodendritic compartments where it interacts with various proteins and the plasma membrane to modulate a wide variety of processes and signaling pathways (Tashiro et al. (1997); Maas et al. (2000); Avila et al. (2004); Morris et al. (2011)). Tau is highly abundant in axons (Mandell and Banker (1995); Dotti et al. (1987); Trojanski et al. (1989); Litman et al. (1993)), where it facilitates tubulin assembly by nucleating, bundling and stabilizing microtubules. Tau also binds to actin, influencing polymerization, and might orchestrate the interaction of microtubules and actin polymers in the organization of the cytoskeletal network (Kotani et al. (1985); Fulga et al. (2007); He et al. (2009); Farias et al. (2002)). By binding to sites on tubulin that overlap with those of other proteins, such as the molecular motor kinesin, tau can also influence axonal transport (Ebneth et al. (1998); Terwel et al. (2002)). Finally, tau may also play a role in neurogenesis (Bullmann et al. (2007); Hong et al. (2010)).
Since tau has numerous functions, it likely contributes to neurodegeneration in multiple ways, including both gain- and loss-of-function effects. Under pathological conditions, tau becomes hyperphosphorylated (Lippens et al. (2012)), aggregated (Mandelkow and Mandelkow (2012); Hernandez and Avila (2008)) and disseminated to neighboring neurons (Le et al, (2012); Santa-Maria et al. (2012)(2)). How this occurs in the absence of coding region mutation or imbalances in alternative splicing is not clear, but secondary post-translational modification plays a role (Lippens et al. (2012); Mandelkow and Mandelkow (2012)). Alternatively, accumulation of abnormal tau protein could be facilitated by failure in protein degradation systems (Wang and Mandelkow (2012)). One additional mechanism that has not been directly addressed is whether increased tau synthesis stemming from dysregulation of tau translation by microRNAs plays a role in tauopathy.
MicroRNAs are small non-coding RNAs averaging 22 nucleotides that regulate the expression of their target mRNA transcripts (Ambros (2004); Bartel (2009), and likely play a role in brain aging, neurodegeneration and neuroprotection (Kosik (2006); Saugstad (2010); Abe and Bonini (2013); Gascon and Gao (2012); Schonrock and Gotz (2012)). Mature microRNAs are derived from 70-100 bp precursors that are consecutively processed by the type III RNases, Drosha and Dicer, in the nucleus and the cytoplasm, respectively (Perron and Provost (2009)). RNA strands are then incorporated into the RNA-induced silencing complex. Binding of microRNAs to their targets is specified by complementary base pairing between positions 2-8 of the microRNA and the target 3′ untranslated region (3′ UTR) (Bartel (2009), an mRNA component that influences translation, stability and localization (Mazumder et al. (2003)); Kuersten and Goodwin (2003); Matoulkova et al. (2012). The precise mechanism whereby microRNAs silence their targets is under debate (Eulalio et al. (2008); Flynt and Lai (2008)).
While tau is regulated post-transcriptionally, it is not known whether microRNAs play a direct role.